Retroviral infections of vertebrates are associated with various manifestations including the development of lymphoma or immunodeficiency. The studies in this project are focused on a unique set of mouse retroviruses that induce both disease phenotypes with immunodeficiency developing within a few weeks after infection and lymphoma at 12 or more weeks. The etiologic agent in both diseases appears to be a replication-defective virus (BM5def) that encodes only a variant Gag protein. Infection with BM5def pesudotyped with nonpathogenic helper viruses leads to marked changes in cytokine production. Mice infected with BM5def have increased transcripts for both Th1 and Th2 cytokines. We showed expression of the Th2 cytokines to be an epiphenomenon of infection whereas expression of IFNg was crucial for rapid progression of lymphoproliferation. Examination of IFN signaling pathways showed that expression of members of the interferon response factor (IRF) family was blocked at the level of translation or phosphorylation and that mice completely deficient in one member, ICSB, did not develop MAIDS. Alterations in B cell signaling were also evident as mice deficient in IL-4 made high levels of IgE after infection. This effect may be due to the interaction of BM5def Gag with normal cellular proteins. The yeast two hybrid system was used to define proteins that bind to Gag. Ten different genes have been identified with one being KIF4, a kinesin motor protein. KIF4 may bind to Gag on vesicles and thus be important for transport of Gag proteins to the cell surface. This may provide a new target for interference with the retrovirus life cycle.